Biologics with Potential
Companies are increasingly looking toward mAbs to overcome the challenges that small molecules and peptides have had with treating neurodegenerative diseases. The mAb candidates are being directed against components of the plaques characteristic of AD and other neurodegenerative diseases. The plaques are believed to play a fundamental role in their etiology and pathology.
This year may see the emergence of one of these novel mAb-based drugs. Among these are Lilly’s solanezumab, a humanized antibody that binds to soluble β-amyloid resulting in a reduction of amyloid plaque formation. Lilly began enrolling patients in two separate but identical Phase III trials in May 2009. The objective of the 18-month trials, expected to enroll a total of 2,000 patients age 55 and over, was to test whether solanezumab could slow the cognitive and functional decline of mild-to-moderate Alzheimer disease patients compared with placebo.
Analysts predict that even modest success for solanezumab in these trials will bode well for an entirely new class of drugs that can modify the disease itself instead of treating the symptoms. The total Alzheimer disease drug market is expected to nearly triple over the next decade, increasing from $5.4 billion in 2010 to $14.4 billion in 2020 in the U.S., France, Germany, Italy, Spain, the U.K., and Japan.
Lilly is expected to release final data from the trials this summer. This combined with the commercial launch of Amyvid puts Lilly in the completely unique position of owning both a diagnostic aid and a treatment for AD.
Another viable mAb therapeutic candidate for AD is bapineuzumab, being jointly developed by Elan, Johnson & Johnson, and Wyeth (now owned by Pfizer). Preliminary findings from a Phase II study reported in 2008 pointed to the candidate’s efficacy in clinical activity in noncarriers of the apolipoprotein E4 (ApoE4) allele, estimated to exist in 40% to 70% of AD patients. ApoE4 is a known genetic risk factor for development of AD.
A study reported in 2009 concluded that the primary efficacy outcomes in the Phase II trial were not significant and that treatment differences in the exploratory analyses “supported further investigation of bapineuzumab in Phase III with special attention to APOE ε4 carrier status.”
Other analyses of patients in the same studies found that treatment with bapineuzumab decreased levels of total and phosphorylated tau in the cerebrospinal fluid of patients with mild-to-moderate disease. Tau is another protein player thought to participate in plaque formation.
“This study provides support that anti-amyloid immunotherapy may affect the degenerative process in AD,” Kaj Blennow, M.D., Ph.D., of the clinical neurochemistry laboratory, University of Gothenburg, said in an interview with Medscape Medical News.
The study authors wrote that “the CSF level of P-tau thus seems to reflect the phosphorylation state of tau and the formation of tangles in the brain. The reduction in the downstream biomarker CSF P-tau following treatment with bapineuzumab suggests that bapineuzumab reduces brain levels of P-tau, which may also reduce the formation of tangles in the brain.”
But the authors also noted that “an important question remains whether such changes in CSF biomarkers correlate with clinical benefit. This question will be addressed in the ongoing bapineuzumab Phase III trials.”
Biogen Idec, meanwhile, is also pursuing biologics as a means of treating neurodegenerative disorders. In 2010, it acquired a subsidiary of Neurimmune and with it the worldwide rights to three preclinical immunotherapy programs for an initial payment of $32.5 million and up to $395 million in contingency fees. The three programs focus on human antibodies that target the proteins alpha-synuclein, tau, and TDP-43. All three targets are considered relevant for treating and preventing several neurodegenerative diseases including AD, PD, and amyotrophic lateral sclerosis.
Development of a treatment for AD and other neurodegenerative diseases remains a brass ring for the pharmaceutical industry. It is one of the few therapeutic areas, some analysts have said, where a new drug could achieve blockbuster status.
Questions about clinical benefits of preventing plaque formation, either through interfering with plaques themselves or with their potential components, will haunt the development of any biological aimed at them. As data from such antibody studies emerges in the third quarter of this year, clear clinical evidence may establish the value of inhibiting the plaque formation thought to kill brain cells.
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